We have previously shown that overexpression of c-myc and transforming growth factor-alpha (TGF-alpha) in the liver of double transgenic mice results in severe DNA damage, aberrant hepatic growth and development of tumors at a much younger age than that observed in c-myc single transgenic mice. We now report that double transgenic TGF-alpha/c-myc hepatocytes rapidly lose their ability to proliferate upon mitogenic stimulation following partial hepatectomy (PH). At four weeks of age, the overall rate of BrdU-incorporation following PH was comparable in c-myc and TGF-alpha/c-myc livers and exceeded that seen in wild type (WT) mice. However, by 10 weeks of age c-myc single transgenic hepatocytes demonstrated proliferative advantages over the WT cells whereas TGF-alpha/c-myc double transgenic hepatocytes had a decreased capacity to proliferate upon mitogenic stimulation. This decreased proliferative response was accompanied by a reduction in the total fraction of proliferating hepatocytes as well as by a decline in the induction of cyclin A, cyclin B and cdc2 gene expression. These data show that constitutive coexpression of c-myc and TGF-alpha accelerates age-related loss in the regenerative potential following PH and suggest that early replicative senescence of differentiated hepatocytes may have a role in providing a selective growth advantage to initiated cell populations in this model.